Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12]/[C:11](=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:25])([CH3:24])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:25])([CH3:24])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:31]=[C:32]([F:37])[CH:33]=[C:34]([F:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC/C=C1/C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCC1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1

Procedure:
Combine (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-hex-(Z)-ylidene-pyrrolidine-1-carboxylic acid tert-butyl ester (0.04 g, 0.076 mmol), 10% palladium on carbon (4 mg) and methanol (2 mL) and stir for 2 days under 1 atmosphere of hydrogen. Add filter agent, filter and concentrate under reduced pressure to provide the desired compound as a mixture of isomers (2:1 4(S):4(R); 0.036 g, 90%). Subject isomer mixture to HPLC chromatography under acidic conditions: TFA 0.05% at pH 2.5; Organic solvent: acetonitrile; Gradient from 90 to 95% acetonitrile.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[N+:37]([O-:39])=[O:38])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[N+:37]([O-:39])=[O:38])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Reactant: OC1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and adtition funnel. A solution of 2-nitro-5-(2-nitro-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-nitro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13]2)[CH:3]=1.C[CH2:33][N:34](C(C)C)C(C)C.CN>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:34][CH3:33])[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13]2)[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Agent: CN
Solvent: C1COCCO1
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Into a 100 mL RB flask was dissolved cis-1-[6-chloro-2-(methylsulfonyl)-4-pyrimidinyl]-N-(phenylmethyl)-6-(trifluoromethyl)-3-piperidinecarboxamide (400 mg, 0.839 mmol) in 1,4-dioxane (5 mL), then added Hunig's base (0.730 mL, 4.19 mmol), and the resulting mixture was stirred for 5 minutes. Methylamine (1.677 mL, 3.35 mmol, 2M in THF) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and then CH3OH (15 mL) was added. An insoluble solid was observed and the mixture was filtered. The filtrate was concentrated to afford the title compound (301 mg) as a clear oil. LC-MS (ES) m/z=428 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>C1COCC1>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH2:29][CH2:30][NH:31][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: NCCNc1nc2ccccc2s1
Reactant: O=c1[nH]nc2c(Br)nc(-c3ccc(Cl)cc3)cn12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc2c(NCCNc3nc4ccccc4s3)nc(-c3ccc(Cl)cc3)cn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 50 mg of the product of Step A, 43 mg of N1-benzothiazol-2-yl-ethane-1,2-diamine, and 124 mg of triethylamine in THF (1.0 mL) was heated to reflux. After 16 h, the reaction mixture was cooled to ambient temperature and then partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to a residue that was purified by silica gel chromatography to afford the title compound as a white solid. MS (M+H+)=438.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:41](=[O:43])[CH3:42])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N(C(C)=O)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 3 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol), triethylamine (1 mL) and acetyl chloride (116 μL, 1.64 mmol) in 1,4-dioxane (10 mL). The title compound was obtained as a white solid (69 mg, 31.8%). The title compound was characterized by LCMS and 1H NMR as shown below:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH3:8].[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N)nccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N
Product: Nc1nccc2cc(O[C@H]3CCCNC3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 1 %

Procedure:
A mixture of (S)-3-(1-amino-isoquinolin-6-yloxy)piperidin-1-carboxylic acid tert-butyl ester (72 mg) in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) was stirred at ambient temperature for 1.5 h. The mixture was concentrated in vacuo then flash chromatography of the residue (eluent: 2-10% methanol in dichloromethane with 1% aqueous ammonia) gave (S)-6-(piperidin-3-yloxy)-isoquinolin-1-ylamine, El-MS: m/z=244.4 [M+H]+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH3:3].C(N(CC)CC)C.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].C(OCC)(=[O:27])C>O1CCCC1.O>[C:13](=[O:27])([O:14][CH2:1][CH2:2][CH3:3])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Reactant: CCCO
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a solution of 0.75 g of propanol and 1.90 mL of triethylamine in 10 mL of tetrahydrofuran, a solution of 2.50 g of 4-nitrophenyl chloroformate in 15 mL of tetrahydrofuran was dropped under cooling on ice. After stirring at room temperature for 20 min, ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution successively, dried over anhydrous magnesium sulfate, followed by solvent removal by evaporation under reduced pressure. To the residue, hexane was added, and insoluble matters were removed by filtration. After removing the solvent by evaporation under reduced pressure, 2.59 g of 4-nitrophenyl propyl carbonate was obtained as a light yellow oily matter.
Reaction SMILES: CC([O-])(C)C.[K+].CC(O)(C)C.[CH2:12]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[C:13]=[CH2:14]
Reactant: C#CCOc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: C=C=COc1cccc2ccccc12
Yield: 43 %

Procedure:
Into a similar reaction vessel as used in the abovementioned reaction, were placed 1.532 parts of t-BuOK and 6.816 parts of t-BuOH and to this, a mixture of 10.000 parts of 1-propargyloxynaphthalene and 23.333 parts of t-BuOH was dropwise added. The content was reacted at 50° C. for 60 minutes and then deionized water was added to stop the reaction. t-BuOH layer and water layer were removed off by using an evaporator, and the residue was added with an aqueous NaOH solution, extracted with an ether and the ether layer was separated. The ether solvent was removed off and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1-allenyloxy naphthalene as a colorless oily product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[CH3:30][O:31][NH:32][CH3:33]>S(Cl)(Cl)=O>[CH3:30][O:31][N:32]([CH3:33])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CNOC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(Quinolin-2-ylmethoxy)-benzoic acid (25.98 g, 93 mmole) was added 250 ml of thionyl chloride under N2. The reaction mixture stirred 3 h and the excess thionyl chloride was removed under vacuum. The acid chloride was dissolved in tetrahydrofuran (450 ml) and triethylamine (50 ml, 4 eq.) was slowly added. O,N-dimethyl hydroxyl amine hydrochloride (27 g, 3 eq.) was added and the reaction stirred 18 h. The reaction mixture was placed on a rotovap to remove the solvent, partitioned between 1N NaOH and methylene chloride, separated, dried magnesium sulfate, filtered and concentrated. The crude product was filtered through silica gel eluting with 30-70% ethyl acetate/hexane to proved the title compound as a brown oil (26.26 g, 87%); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=8.7 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.67 (m, 3 H), 7.63 (d, J=8.3 Hz, 1 H), 7.52 (m, 1 H), 7.01 (M, 2 H), 5.39 (s, 2 H), 3.52 (s, 3 H) 3.31 (s, 2H); MS: (M+H m/z=323.2).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]>>[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:10]/[CH:9]=[C:6]2/[CH2:7][N:8]3[C@H:4]([O:5]/2)[CH2:3][C:2]3=[O:1])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Product: CC(=O)Nc1ccc(SC/C=C2/CN3C(=O)C[C@H]3O2)cc1

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (2.6 mmole) and p-acetamidophenyl mercaptan (0.5 g) were converted into the title compound using the process described in Example 1. The title compound was obtained as a colourless gum (102 mg), [α]D25 =+39.3° (c 1.0, CHCl3), (Found: M+ ; 304.0896; C15H16N2O3S requires 304.0882). νmax (CHCl3): 3380, 3280, 1790, 1720, 1690 (sh), 1665, 1590, 1496 cm-1. δ(CDCl3): 2.08 (3H, s), 2.60-3.50 (5H, complex), 4.18 (1H, d, J 14 Hz), 4.35 (1H, t, J 7 Hz), 5.30 (1H, d, J 2 Hz), 7.10-7.40 (4H, complex), 7.80 (1H, br.s). m/e: 304 (M+, 12%), 138 (100), 96 (62).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:11][CH:10]=1)=[O:8].CI.[CH:38](N(C(C)C)CC)(C)C>ClCCl>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4)cc2)CCO3)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Temperature: 25 °C

Procedure:
In dichloromethane (35 ml) was dissolved N-(4—(piperidin-2-ylcarbonyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.3 g), and to the solution were added methyl iodide (0.08 ml) and diisopropylethylamine (0.17 ml). The mixture was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—(1-methylpiperidin-2-ylcarbonyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 157) (0.17 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)N1C=CC=CC1.[NH2:43][C:44](=[N:48]O)[C:45]([NH2:47])=[O:46]>CN(C)C=O>[NH2:48]/[C:44](=[N:43]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[C:45]([NH2:47])=[O:46]
Reactant: NC(=O)C(N)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CN(C)N1C=CC=CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (3.47 g, 11.6 mmol) in dimethylformamide (21 ml) was treated with 1,1′-carbonyidiimidazole (1.97 g, 12.2 mmol) and the mixture was stirred at ambient temperature for 1 hour. N-Dimethylaminopyridine (1.43 g, 11.7 mmol) was then added in one portion, followed by the addition of 2-amino-2-(hydroxyimino)acetamide (1.25 g, 12.1 mmol, Helv.Chim.Acta; 47; 1964; 33-46). The resulting mixture was stirred at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and a 10% solution of citric acid in demineralised water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with demineralised water (×4) and brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was crystallised from n-hexane, the precipitate was collected by filtration and dried in vacuo to afford the title compound as a colourless solid (3.30 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(OC)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-methoxybenzenesulfonyl chloride according to METHOD A, giving 9.83 g (55%) of pure material: MS (Ionspray, [M+H]+) m/z 356; Anal. Calcd. (found) for C14H16N2O5S2: C, 47.2 (47.1)%; H, 4.5 (4.5)%; N, 7.9 (7.8)%.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20]C3C=CC(Cl)=CC=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](OCC)=O)=[CH:33][CH:32]=1.FC(F)(F)C1C=CC(CC(OCC)=O)=CC=1.C(N)CC1C=CC=CC=1.ClC1C=CC(N)=CC=1>>[C:3]1([CH3:2])[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=c1c(-c2ccc(C(F)(F)F)cc2)c[nH]c2ccnc(Nc3ccc(Cl)cc3)c12
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: NCCc1ccccc1
Agent: Nc1ccc(Cl)cc1
Product: Cc1ccc(-c2c[nH]c3ccnc(NCCc4ccccc4)c3c2=O)cc1

Procedure:
3-(4-Trifluoromethylphenyl)-1,4-dihydro-4-oxo-5-(4-chlorophenylamino)-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that ethyl (4-chlorophenyl)acetate was replaced with ethyl (4-trifluoromethyl-phenyl)acetate and phenethylamine was replaced with 4-chloroaniline. MS 416 (M+1)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[O:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCCl>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)CCCOc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCCOc1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
25.6 g of anhydrous aluminum trichloride are suspended in 64 ml of 1,2-dichloroethane, and 28.6 g of 4-methoxybenzoyl chloride are added. Then, while stirring vigorously, 31 g of methyl 4-phenoxybutyrate are slowly added. The reaction mixture is subsequently stirred at 50° C. for 4 hours, allowed to cool and poured into ice-water. The oily organic layer and the aqueous phase are separated, the organic phase is washed with water, and a little methanol is added to induce crystallization. The product which has separated out is filtered off with suction and recrystallized from ethyl acetate.
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[Na].[C:31]([O:35][CH3:36])(=[O:34])[CH2:32][SH:33]>CO>[CH3:36][O:35][C:31]([CH2:32][S:33][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:34]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CO
Product: COC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1.93 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 100 ml of methanol is added a solution of 0.64 g of methyl thioglycolate sodium salt with stirring under ice-cooling. After 1 hour, the solvent is distilled off and the residue is dissolved in ethyl acetate. The solution is washed with water, then the solvent is distilled off, and the residue is purified by silica gel column-chromatography (methylene chloride: ethyl acetate=11:1) to give 1.38 g of (3R,4R)-4-methoxycarbonylmethylthio-3-tritylamino-2-oxoazetidine (A) and 0.92 g of the corresponding (3R,4S)-isomer (B)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([B:10]([OH:12])[OH:11])=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: COc1ccc(B(O)O)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(B(O)O)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 3-amino-4-methoxyphenylboronic acid (1 eq, 2.10 mmol, 0.35 g) in CH2Cl2 (5 mL) at −78° C. was added Et3N (6 eq, 13.0 mmol, 1.7 mL). The reaction was stirred for 30 minutes then methanesulfonyl chloride (1.1 eq, 2.30 mmol, 0.26 g) was added. The reaction was then stirred at −78° C. for 1 hour. The reaction was allowed to warm to room temperature and diluted with CH2Cl2. The reaction washed with 1.0N aqueous HCl and the organic phase was extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 4-methoxy-3-(methylsulfonamido)phenylboronic acid (1.92 mmol, 0.49 g, 96%) as a white solid.
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=[C:3]([C:12]([O:14]CC)=[O:13])[N:2]=1.Cl>C(O)C.[OH-].[Na+].CCOCC>[CH2:10]([O:9][C:7]([C:6]1[N:1]=[N:2][C:3]([C:12]([OH:14])=[O:13])=[CH:4][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=O)O)nn1
Reaction time: 2 h

Procedure:
To the diethyl 3,6-pyridazinedicarboxylate (5.0 g, 22.3 mmol) in 150 ml ethyl alcohol, 24.5 ml 1N NaOH was added. The mixture was stirred for 2 hours. The resulting salt was collected by filtration then was dissolved in minimum amount of water. The aqueous solution obtained was then acidified with 2N HCl in ether until the PH=2 and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent afforded 4.1 g of light yellowish oil. 1HNMR (400 MHz, CD3OD) δ 8.42 (s, 2H), 4.52 (q, 2H), 1.42 (t, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[N:26]=[C:25]([NH2:36])[N:24]=1)[CH2:19][NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>C(#N)C>[NH2:36][C:25]1[N:24]=[C:23]([C:22]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:10])[CH2:19]3)=[CH:14][C:13]=2[CH3:12])[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[N:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CN(C(=O)Nc1ccc(Cl)cc1)CC2
Reaction time: 0.5 h

Procedure:
1-Chloro-4-isocyanatobenzene (4.1 mg, 0.026 mmol) was added to a mixture of 4-(6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (15 uL, 0.11 mmol) in acetonitrile (0.3 mL). After 30 min., the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=492.2/494.1.